Venance

Dynamic and Pathophysiology of Neuronal Networks

Principal Investigator: Laurent VENANCE, DR2 Inserm

Our research targets the motor control and the encoding of procedural learning, which corresponds to the acquisition of skills through repeated performance and practice of a behavior in response to external cues (Fig. 1). Basal ganglia are central in procedural learning since they participate in the detection of environmental cues and in the selection of appropriate actions based on motivation and reward. The key roles of basal ganglia are highlighted by motor and cognitive disorders observed in different pathologies such as Parkinson's disease or addiction, for which no fully satisfying treatments are available yet.

In fundamental and pathological perspectives, our team studies the functional organization and dynamics of the basal ganglia network. For this purpose, it is necessary to characterize: (1) input processing, i.e. how cortical information are selected and integrated in this network, (2) trans-nuclei processing, i.e. how information is relayed toward the basal ganglia output structures to trigger an appropriate behavior and finally (3) the modulation, i.e. how this integration is sculpted by the main neuromodulatory systems, dopaminergic and cholinergic systems, which encode for reward and motivation and how it is altered in pathological conditions. For this purpose, we are using a set of high-performance techniques combining in vitro (multi-patch-clamp in brain slices) and in vivo (intra- and extracellular recordings) electrophysiology, single-cell RT-PCR, neurochemistry and genetic engineering. We are currently setting-up in vitro and in vivo two-photon microscopy, optogenetic and multi-channels recordings in behaving rodents (see Projects).

The complementary expertise of the members of the team together with the collaborations with mathematicians and clinicians allow us to investigate basic and translational aspects. The three main programs developed in our lab for the past 5 years are the followings:

(1) Cortex-basal ganglia input processing.

Cortical afferents are functionally organized from limbic to sensorimotor areas and enter basal ganglia through two input nuclei: the striatum and the subthalamic nucleus.

a) The cortico-striatal pathway. The striatum acts as a coincidence detector of cortical inputs and extracts relevant information from background noise in relation with the environmental stimuli and motivation. Therefore, the striatum is a major site of memory formation for sensorimotor and cognitive associations. We demonstrated the existence of a bidirectional long-term synaptic plasticity and pioneered the field of spike-timing dependent plasticity (STDP) at cortico-striatal synapses. We characterized the properties and the signaling pathways involved in STDP at striatal output neurons and interneurons (Fig. 2). This thorough characterization led us proposing a new model in which the different striatal subpopulations would act synergistically to increase or decrease the striatal output depending on the temporal activation sequence of the cortex/striatum couple.

Figure 2: (A) Interactions between striatal interneurons (cholinergic: Chol, fast-spiking GABAergic: FS and NO-synthase containing interneuron: nNOS) and striatal output neurons (MSNs). (B-D): Cell-specificity of STDP among striatal neurons. (B) Representative plasticity induced in FS GABAergic interneurons: post-pre pairings induced a LTD whereas pre-post pairings lead to a LTP. (C) Summary of the long-term synaptic plasticity for different temporal windows tested in FS interneurons. Each grey dot represents the plasticity in one interneuron measured at 60 min after the pairing protocol (as indicated by "a" and "b" on the graphs in B). (D) Cell-specificity of the striatal plasticity: the orientation and temporal windows of the STDP are different for each striatal neuronal subtypes (from Fino and Venance, 2011).

b) The cortico-subthalamic pathway. The cortico-subthalamic pathway is a central piece of basal ganglia computational models but has been poorly characterized experimentally. Thanks to new a brain slice where cortico-subthalamo-nigral connections were preserved, we showed that the rules of frequency- and timing-dependent plasticities are strikingly different from the cortico-striatal pathway, highlighting the distinct functional roles of the two basal ganglia input pathways.

Cortical information is processed through three main pathways (hyperdirect, direct and indirect) towards the basal ganglia output nuclei to trigger adapted behaviors. The hyperdirect pathway turns off ongoing motor programs, allowing the direct pathway to select the goal-directed behavior and the indirect pathway ends the action. We showed that these three pathways are sequentially activated since in vivo cortical stimulation induces a triphasic synaptic response in the basal ganglia output structures. This triphasic response is a powerful readout of the whole information processing in the cortico-basal ganglia loop in physiological and pathophysiological conditions.

(3) Pathophysiological neuromodulation of inputs/ouputs of the basal ganglia.

We investigated the two main neuromodulatory systems within basal ganglia, i.e. dopamine and acetylcholine. They are deeply affected in Parkinson's disease and motor stereotypies. We investigated the mechanisms and circuits involved in the control of pathological neuronal activities and the modifications by which pharmacological treatments and electrical stimulation (deep brain stimulation) normalize these activities.

In conclusion, we studied various aspects of the functional organization and synaptic interactions underlying the dynamic properties of the basal ganglia network and the changes of these properties in animal models of human pathologies. Notably, we have (1) pioneered the field of cortico-striatal spike-timing dependent plasticity, (2) characterized the triphasic response as a powerful readout of basal ganglia information processing and (3) explore the beneficial effect of pharmacological and electrical treatments in Parkinson's disease and motor stereotypies.